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Abstract:

Methods for making Imatinib mesylate of formula (I):
##STR00001##
having low levels of organic solvent are provided. Also provided are
alpha and beta forms of Imatinib mesylate and methods for treating
conditions such as chronic myelogenous leukaemia by administering same.

Claims:

1. A method for the preparation of Imatinib mesylate of formula (I):
##STR00006## comprising introducing a suspension of Imatinib mesylate in
an organic solvent into a crusher/disperser comprising one or more stator
combinations and one or more rotors.

2. The method of claim 1, wherein one or more rotors are set at a speed
between about 1000 and about 100,000 rpm.

3. The method of claim 1, wherein the Imatinib mesylate is subjected to a
tip speed of around 23 m/s.

4. The method of claim 1, wherein said method is performed between about
5 and about 60 minutes.

5. The method of claim 4, wherein said method is performed for about 15
minutes.

6. The method of claim 1, wherein the organic solvent is selected from
the group consisting of: alcohols, ketones, acetates and ethers.

7. The method of claim 6, wherein the organic solvent is a C1-C5 alcohol.

8. The method of claim 7, wherein the organic solvent is selected from
the group consisting of: ethanol, isopropanol, and n-butanol.

9. A Imatinib mesylate compound of formula (I): ##STR00007## comprising
between about 1000 and about 5000 ppm of an organic solvent selected from
the group consisting of: ethanol, propanol, butanol and pentanol.

10. The Imatinib mesylate of claim 9, wherein the propanol is selected
from the group consisting of: n-propanol and isopropanol; the butanol is
selected from the group consisting of: n-butanol, isobutanol,
sec-Butanol, tert-Butanol; and the pentanol is selected from the group
consisting of: n-pentanol, isopentanol and sec-pentanol.

11. The Imatinib mesylate of claim 9, comprising n-butanol.

12. The Imatinib mesylate of claim 11, comprising between about 2000 and
about 4000 ppm of n-butanol.

13. The Imatinib mesylate of claim 9, wherein the Imatinib mesylate is in
the alpha polymorphic form or the beta polymorphic form.

14. A pharmaceutical composition comprising the Imatinib mesylate of
claim 9 and one or more acceptable pharmaceutical excipients.

15. A method for treating chronic myelogenous leukaemia comprising the
administration of the compound of claim 9 to a subject in need of such
treatment.

16. A method for preparing Imatinib mesylate having less than 5000 ppm of
a residual organic solvent comprising use of a crusher/disperser having
one or more stator combinations and one or more rotors.

Description:

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and benefit of Italian Patent
Application No. MI2011A001309 filed Jul. 14, 2011, the contents of which
are incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to methods for the preparation of
Imatinib mesylate.

BACKGROUND OF THE INVENTION

[0003] Imatinib mesylate, compound of formula (I), is an important active
ingredient used to treat chronic myelogenous leukaemia.

##STR00002##

[0004] Its preparation was described for the first time in Novartis' EP
564409 and subsequently in EP998473 where the preparation of Imatinib
mesylate alpha and beta polymorphic form are described. An interesting
and inexpensive procedure for the preparation of the key intermediate is
described in WO2008/059551 in the name of F.I.S. Fabbrica Italiana
Sintetici S.p.A. Also described are other preparations of polymorphic
forms of Imatinib mesylate, in particular the alpha and beta forms, in
WO2006/024863, US2006/0223816, WO2008/150481 and WO2009/151899. None of
these references discuss the significant problem relating to residual
solvents. Such residual solvents do in fact represent impurities of the
active ingredient and of the formulated product like typical organic
impurities. Such impurities to conform to ICH and related national and
European guidelines, must be quantified and comply with the relative
limits.

SUMMARY OF THE INVENTION

[0005] The problem addressed by the present invention is therefore that of
providing a procedure for the preparation of Imatinib mesylate of formula
(I) having a residual solvent content in conformity with current ICH
guidelines and regulatory standards throughout the world.

[0006] Such problem is solved by methods for the synthesis of Imatinib
mesylate as described herein and in the claims.

BRIEF DESCRIPTION OF THE FIGURES

[0007] FIG. 1 illustrates the rotor-stator principle,

[0008] FIG. 2 shows an embodiment of the present invention at laboratory
scale with an appropriate disperser.

[0009] FIG. 3 illustrates a part of an industrial disperser wherein the
three in-series rotor-stator combinations can be seen, which facilitate
the breaking up into small pieces and the homogenization of the product
in suspension.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention relates to methods for the preparation of
Imatinib mesylate of formula (I):

##STR00003##

having a residual solvent content in compliance with the guidelines of
the ICH (International Conference of Harmonization) Q3C(R4) (Impurities:
guideline for Residual Solvents) published in February 2009. A particular
reference is made with respect to the solvents classified in Class 3 for
which a residual solvent limit of 5000 ppm is required.

[0011] Experimentally repeating the preparatory methods described in the
current state of the art, though obtaining the product in the alpha and
beta polymorphic forms, the problem of the residual solvent content was
consistently greater than the ICH limits. The problem was evident even
when different types of solvents were used, e.g., alcohols, ketones,
acetates, ethers, etc. It was then unexpectedly discovered that by
treating a suspension of Imatinib mesylate in an organic solvent with a
disperser or crusher comprising one or more stator combinations and one
or more rotors, Imatinib mesylate can be obtained having residual
solvents in compliance with the ICH guidelines and pharmacopoeias.

[0012] By preparing Imatinib mesylate, in both alpha and beta polymorphic
form, e.g., crystallizing or re-crystallizing it from n-butanol, a
product is obtained containing over 17000 ppm of residual n-Butanol even
if the product is dried at 60° C. under vacuum for 48 hours. By
drying the product at 120° C. under vacuum for 24 hours or under
nitrogen flow at 90° C., the product still contains 9000-10000 ppm
of residual n-Butanol which is much higher than the 5000 ppm of the ICH
limit. Totally similar problems, with the same levels of residual
solvents, can be observed by crystallizing the product, for example, from
Ethanol, Isopropanol, MEK or MTBE. Using the procedure of the present
invention, employing for example n-butanol, even by drying the product at
just 60°-80° C. for 10-12 hours, Imatinib mesylate may be
obtained having less than 5000 ppm of n-Butanol, normally around 3000 ppm
and in any case always above 1000 ppm and below 5000 ppm, and is
therefore in compliance with the current ICH limits for such solvent.

[0013] Without being bound by the following theory, a possible scientific
explanation of the effect of the present invention has been found by
discovering that the product crystallizes by combining solvent molecules
inside the crystal aggregates. It has thus also been confirmed by means
of DSC and TGA measurements that the solvent does not enter the crystal
lattice to form a solvated species. Instead solvent is simply combined in
the crystal aggregate. Nevertheless it is very difficult to remove or
bring it within permitted limits using conventional drying methods. On an
industrial scale, the problem of drying the product in such a way as to
lead to a product of pharmaceutically acceptable grade has dragged on for
quite a long time without any industrially viable solutions being found.

[0014] The procedure of the present invention is therefore achieved by a
treatment of a suspension of Imatinib mesylate with a crusher or
disperser able to break down the particles of product in suspension. The
grinding treatment carried out on the solid dried or partially dried
product does not produce the same results inasmuch as the quantities of
residual solvents remain high.

[0015] Appliances have been available for a long time at both laboratory
level and industrial level which are able to perform this product
dispersion procedure by splittin up and distributing the solid in the
liquid phase, thereby obtaining a homogeneous suspension. The principle
on which these appliances are based is called rotor-stator principle and
is exemplified in FIG. 1 and summed up as follows. The high number of rpm
of the rotor axially sucks up the fluid into the dispersion head and is
then pushed radially through the slots of the rotor-stator. The strong
accelerating forces apply very strong tension and thrust forces on the
material. In addition, in the slot between the rotor and the stator, a
strong turbulence is produced that causes the suspension to mix in the
best possible way. These types of appliances can be called dispersers,
crushers, homogenizers or, simply, mixers.

[0016] Methods of the present invention may utilize a crusher/disperser
which comprises one or more stator combinations and one or more rotors
and operates between about 1000 and about 100,000 rpm.

[0017] For laboratory applications, the best tip speed of the rotor-stator
system is around 6-30 m/s, preferably about 23 m/s and rotor ranges of
between about 3000 and about 30,000 rpm. Imatinib mesylate therefore may
be subjected to such tip speed and rotor rpm values. In the case of
industrial applications, speeds of up to 100,000 rpm can even be reached,
even though, especially for very large scales, rotor speeds of 1000-2000
rpm are normally applied.

[0019] For laboratory applications in general, a treatment time of just a
few minutes is enough to achieve the required end fineness. Longer
treatment times only provide marginal improvement to the fineness of the
materials and consequently 15-minute treatments are normally enough.

[0020] A specific type of laboratory equipment suitable for methods
according to the present invention is the IKA ULTRA-TURRAX T25 digital.

[0021] In this appliance (FIG. 2) there is just one rotor-stator
combination.

[0022] For industrial applications, the IKA® Dispax Reactor model DR
2000/10 Disperser is particularly effective inasmuch as it has a 3-stage
rotor-stator system consisting of 3 rotor-stator combinations in series.
(See FIG. 3.) Such industrial appliances also take the name of "wet
mill".

[0023] For laboratory-scale preparations, the procedure may be performed
with treatment times between about 5 and about 60 minutes. In certain
embodiments, the treatment time may be about 15 minutes.

[0024] The organic solvent in which the Imatinib mesylate can be
conveniently suspended or may be obtained may be chosen from among
alcohols, ketones, acetates and ethers. For example, the Imatinib
mesylate may be suspended in a C1-C5 alcohol and therefore in an alcohol
chosen from among methanol, ethanol, n-propanol, isopropanol, n-butanol,
sec-butanol, isobutanol, tert-butanol, n-pentanol, 2-ethy-1-1-propanol,
2-methy-1-1-butanol, 3-methy-1-1-butanol, isopentanol, sec-pentanol,
2,2-dimethy-1-1-propanol. In certain embodiments, methods of the present
invention may be conducted by preparing a suspension of Imatinib mesylate
in ethanol or isopropanol or n-butanol.

[0025] In certain embodiments, the methods of the invention may be
conducted by preparing a suspension of Imatinib mesylate in n-butanol.
This solvent has the advantage of allowing slow crystallization, for
example, slower than isopropanol and the other lower alcohols, wherein
the crystallization of the product is very fast. N-butanol, therefore,
permits, depending on the crystallization conditions, obtaining both the
alpha or the beta form of Imatinib mesylate.

[0026] The procedure of the present invention thus allows for the
preparation of Imatinib mesylate of formula (I):

##STR00004##

having between about 1000 and about 5000 ppm of ethanol, propanol,
butanol or pentanol. In particular, propanol may be selected from
n-propanol and isopropanol; butanol may be selected from n-butanol,
isobutanol, sec-butanol, tert-butanol; and pentanol may be selected from
n-pentanol, isopentanol and sec-pentanol.

[0027] In particular, by using n-butanol it is possible to obtain Imatinib
mesylate having a residual content of solvent between about 1000 and
about 5000 ppm and thus in conformity with the present ICH limits and in
certain embodiments between about 2000 and about 4000 ppm.

[0028] Furthermore, the Imatinib mesylate may be obtained in both alpha
and beta polymorphic form (as characterized in EP998473).

[0029] The procedure of the present invention may be applied both during
product crystallization and during a subsequent product
re-crystallization or crushing stage. The content of residual solvents is
an essential characteristic for pharmaceutical products, whether these
are active ingredients or formulated products, inasmuch as compliance
with appropriate limits for pharmaceutical products is obligatory.

[0030] Moreover, Imatinib mesylate obtained according to embodiments of
the present invention by using n-butanol as a crystallization or
recrystallization solvent is free of any detectable amount of the
genotoxic impurity n-butylmesylate. (The detectability threshold is 0.1
ppm.)

[0031] Imatinib mesylate prepared according to methods of the present
invention can therefore be conveniently formulated with one or more
acceptable pharmaceutical excipients. The formulated product may be used
in medicine and, specifically, can be used to cure and/or treat chronic
myelogenous leukaemia.

EXAMPLES

Example 1

Synthesis of Imatinib mesylate (I) Alpha Form

##STR00005##

[0033] In a 20-litre steel vessel 400.0 g of Imatinib base (prepared
according to example 21 of EP0564409) and 8000 ml of n-butanol were
loaded under nitrogen flow and heated under reflux. 20.0 g of Carbon
eno-pc were added and the contents were shaken at reflux temperature for
15 minutes, before filtering on steryflon ptf2071 sl cartridge and
conveying the filtrate by nitrogen thrust to a preheated glass reactor. A
yellowish solution was obtained at pH=6.4. Afterwards, 75.8 g (51.20 ml)
of methanesolfonic acid were dripped in one minute at T=80° C. A
clear solution was obtained at approx. stable 4.5 pH. This was shaken and
left to cool at T=70° C. and primed with 5.0 g of Imatinib
mesylate, alpha form.

[0034] Precipitation with rapid thickening was observed. The solution was
shaken for one hour and left to cool at T=20° C. This was filtered
in 5 minutes and washed with 680.0 ml of n-Butanol. It was then dried in
a vacuum stove at T=50° C. until constant weight, and 315 g of
Imatinib mesylate, alpha form were obtained with a molar yield of 65.7%.
The product contained over 17,000 ppm of residual n-Butanol determined by
GC-HS.

Example 2

Synthesis of Imatinib mesylate (I) Alpha Form

[0035] In a reactor under nitrogen 200.0 g of Imatinib mesylate, obtained
according to Example 1, and 7000 ml of n-Butanol were loaded and this was
heated at reflux before being filtered hot on a dicalite cake. The
filtrate was left to cool to 80° C. at which time 20.0 g of
Imatinib mesylate, alpha form, primer were added and treated for 15
minutes with a high-performance IKA disperser at around 7500 rpm (as
shown in FIG. 2). This was shaken and left to cool at T=40° C. for
30-40 minutes before being filtered and washed with a little n-butanol.
The solid was then dried at 70-80° C. for 10-12 hours. 174.0 g of
product were obtained, equivalent to a molar yield of 79.1%. The content
of residual n-butanol was around 3000 ppm.

Example 3

Synthesis of Imatinib mesylate (I) Beta Form

[0036] The same procedure was followed as described in Example 1 except
that the primer was made with 5.0 g of Imatinib mesylate beta form
instead of alpha form.

[0037] About 318 g of Imatinib mesylate beta form were obtained for a
molar yield of 66.3%.

Example 4

Synthesis of Imatinib Mesylate (I) Beta Form

[0038] The same procedure was followed as described in Example 2 except
that the primer was made with 20.0 g of Imatinib mesylate beta form
instead of alpha form.

[0039] 190.3 g of Imatinib Mesylate Beta form were obtained with a molar
yield of 86.5%.

[0054] The following experimental data were obtained. Further to the
comparison between the first two results (the starting product is the
same for all the subsequent experimental tests), the data show the
difficulties addressed by the present invention.

[0056] It is thus evident that, even if it is known to a person skilled in
the art that reduction in the amount of residual solvents in a product
can be achieved by milling to reduce the particle size, this process is
ineffective with respect to Imatinib masylate. In contrast with most
active agents, Imatinib masylate has the unusual tendency to retain the
residual solvents, particularly alcoholic solvents. Milling does not
provide for an effective reduction of their amount.

[0057] In particular, it should be appreciated that the use of the
conditions forming the subject of the present invention permit obtaining
Imatinib mesylate of formula (I) both in alpha and beta polymorphic form
having a residual solvent content in compliance with ICH guidelines.

Patent applications by Marco Galvagni, Verona IT

Patent applications by F.I.S. FABBRICA ITALIANA SINTETICI S.P.A.

Patent applications in class Additional six-membered hetero ring consisting of five ring carbons and one ring nitrogen attached directly or indirectly to the 1,3-diazine by nonionic bonding

Patent applications in all subclasses Additional six-membered hetero ring consisting of five ring carbons and one ring nitrogen attached directly or indirectly to the 1,3-diazine by nonionic bonding